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0TSC2_HUMAN*   SwissProt (?) | Description Local Annotation Link Reference
General Information
DescriptionTuberin (tuberous sclerosis 2 protein).
SpeciesHomo sapiens (NCBI taxonomy ID: 9606)
GO0005829 cytosol (TAS)
0005624 membrane fraction (TAS)
0005886 plasma membrane (TAS)
0005096 GTPase activator activity (TAS)
0051082 unfolded protein binding (TAS)
0006897 endocytosis (TAS)
0006457 protein folding (TAS)
0000074 regulation of progression through cell cycle (TAS)

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Domain Architecture (Details)
InterPro domains unassigned to SynO:
The Rap/ran-GAP domain is found in the GTPase activating protein (GAP) responsible for the activation of nuclear Ras-related regulatory proteins Rap1.sr1 and Ran in vitro converting it to the putatively inactive GDP-bound state . Ran is an evolutionary conserved member of the Ras superfamily that regulates all receptor-mediated transport between the nucleus and the cytoplasm. RanGAP is a leucine rich repeat containing protein which forms a highly curved crescent. Each LRR forms a short beta-strand and a longer alpha-helix that results in a beta-alpha hairpin motif .The domain is also present in tuberin (a tuberous sclerosis homolog protein) that specifically stimulates the intrinsic GTPase activity of Ras-related protein Rap1A suggesting a possible mechanism for its role in the regulation of cellular growth.
Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by a mutation in either the TSC1 or TSC2 tumour suppressor genes. The disease ischaracterised by hamartomas in one or more organs (including brain.kin.eart and kidney) giving rise to a broad phenotypic spectrum (including seizures.ental retardation.enal dysfunction and dermatological abnormalities . TSC2 encodes tuberin. putative GTPase activating protein for rap1 and rab5. The TSC1 gene was recently identified and codes for hamartin. novel protein with no significant similarity to tuberin or any other known vertebrate protein. Hamartin and tuberin have been shown to associate physically in vivo.heir interaction being mediated by predicted coiled-coil domains. It is thought that hamartin and tuberin function in the same complex.ather than in separate pathways. Moreover.ecause oligomerisation of the hamartin C-terminal coiled coil domain is inhibited by the presence of tuberin.t is possible that tuberin acts as a chaperone.reventing hamartin self-aggregation. Tuberin.s a widely expressed 1784-amino-acid protein . Expression of the wild-type gene in TSC2 mutant tumour cells inhibits proliferation and tumorigenicity. This "suppressor" activity is encoded by a functional domain in the C-terminus that shares similarity with the GTPase activating protein Rap1GAP. Using a yeast two-hybrid assay.he cytosolic found to associate with a distinct domain lying adjacent to the TSC2 GAP similarity region. Rabaptin-5 also binds the active formof GTPase Rab5. It is thought that tuberin may function as a Rab5GAP in vivo to negatively regulate Rab5-GTP activity in endocytosis .
This domain consists of a multi-helical fold comprised of two curved layers of alpha helices arranged in a regular right-handed the repeats that make up this structure are arranged about a common axis . These superhelical structures present an extensive solvent-accessible surface that is well suited to binding large substrates such as proteins and nucleic acids. This topology has been found with a number of repeats and domains.ncluding the armadillo repeat (found in beta-catenins and importins).he HEAT repeat (found in protein phosphatase 2a and initiation factor eIF4G).he PHAT domain (found in Smaug RNA-binding protein).he leucine-rich repeat variant.he Pumilo repeat.nd in the H regulatory subunit of V-type ATPases. The sequence similarity among these different repeats or domains is low.owever they exhibit considerable structural similarity. Furthermore.he number of repeats present in the superhelical structure can vary between orthologues.ndicating that rapid loss/gain of repeats has occurred frequently in evolution. A common phylogenetic origin has been proposed for the armadillo and HEAT repeats .
  IPR011989:Armadillo-like helical
SequencesProtein: TSC2_HUMAN (1807 aa)
mRNA: NM_000548
Local Annotation
Synapse Ontology
endocytosis may be initiated or blocked by all kinds of signal.
sdb:0257 regulation of endocytosis  (Evidence:keywords)
KO assignmentK07207
  Level 3 annotation:
    tuberous sclerosis 2
  Level 2 annotation:
    Insulin signaling pathway
Loci Structure (Details)Loci index, Chromosomal location, Length, Possible relational loci clusterExon1: 53 residues, 2038599-2038755Exon2: 31 residues, 2040401-2040488Exon3: 39 residues, 2043343-2043454Exon4: 50 residues, 2044297-2044442Exon5: 41 residues, 2045403-2045521Exon6: 18 residues, 2046197-2046246Exon7: 44 residues, 2046645-2046771Exon8: 26 residues, 2047106-2047180Exon9: 44 residues, 2048748-2048875Exon10: 50 residues, 2050671-2050815Exon11: 48 residues, 2051872-2052010Exon12: 36 residues, 2052498-2052602Exon13: 29 residues, 2052973-2053055Exon14: 54 residues, 2054273-2054429Exon15: 41 residues, 2055520-2055637Exon16: 43 residues, 2060457-2060580Exon17: 37 residues, 2061511-2061618Exon18: 52 residues, 2061785-2061936Exon19: 43 residues, 2062242-2062365Exon20: 47 residues, 2062850-2062985Exon21: 65 residues, 2064201-2064391Exon22: 33 residues, 2065800-2065894Exon23: 36 residues, 2066069-2066172Exon24: 33 residues, 2066492-2066587Exon25: 45 residues, 2067599-2067728Exon26: 57 residues, 2069033-2069198Exon27: 53 residues, 2069277-2069430Exon28: 39 residues, 2069558-2069671Exon29: 73 residues, 2070166-2070379Exon30: 70 residues, 2071596-2071800Exon31: 25 residues, 2072437-2072506Exon32: 42 residues, 2073696-2073818Exon33: 164 residues, 2074229-2074717Exon34: 27 residues, 2074952-2075028Exon35: 33 residues, 2075231-2075324Exon36: 64 residues, 2076194-2076381Exon37: 48 residues, 2076733-2076873Exon38: 28 residues, 2077864-2077943Exon39: 32 residues, 2078049-2078141Exon40: 35 residues, 2078228-2078327Exon41: 90 residues, 2078447-2078713Exon42: 2 residues, -Jump to TSC2_HUMAN  
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Loci Cluster (Details)Loci: 2909 387192-390754 ~-4K 13162(NME4)(+)Loci: 2910 415668-512481 ~-97K 13166(RAB11FIP3)(+)Loci: 2911 580179-619272 ~-39K 13173(RAB40C)(+)Loci: 4199 774975-778384 ~-3K 13216(-)Loci: 2912 1143241-1211772 ~-69K 13223(CACNA1H)(+)Loci: 2913 1324663-1339443 ~-15K 13234(BAIAP3)(+)Loci: 4200 1435345-1465013 ~-30K 13244(CLCN7)(-)Loci: 2914 1696221-1760318 ~-64K 13253(MAPK8IP3)(+)Loci: 2915 1979968-1984276 ~-4K 13288(SYNGR3)(+)Loci: 2916 2016896-2028484 ~-12K 13290(SLC9A3R2)(+)Loci: 2917 2038599-2078713 ~-40K 13294(TSC2)(+)Loci: 2918 2138651-2144141 ~-5K 13300(RAB26)(+)Loci: 4201 2167184-2186466 ~-19K 13303(CASKIN1)(-)Loci: 4198 357394-360541 ~-3K 13159(MRPL28)(-)Link out to UCSC